Diabetes and Glucose Control
NOTE: Under no circumstances should people suddenly stop taking antidiabetic drugs, especially insulin. Individuals with diabetes should work closely with their healthcare provider before initiating a supplement regimen due to the potential risk of hypoglycemia.
Advanced glycation end products (AGEs) form when sugars bond with proteins, lipids, and nucleic acids. This process contributes to the toxic effects of high blood sugar (Uribarri 2010; Ceriello 2012). Fortunately, several nutrients can counter these processes.
Benfotiamine. Diabetes and obesity often induce a relative thiamine (vitamin B1) deficiency, which contributes to some of the damaging consequences of hyperglycemia (Beltramo 2008; Page 2011; Via 2012). Benfotiamine is a fat-soluble derivative of thiamine that has much greater bioavailability than other forms of thiamine, and is capable of reaching concentrations in the bloodstream several times that of orally administered thiamine (Greb 1998; Xie 2014). This unique form of vitamin B1 inhibits AGE formation, inflammation, and oxidative stress (Hammes 2003; Du 2008; Balakumar 2010; Shoeb 2012).
A clinical trial in 165 patients with diabetic neuropathy found benfotiamine supplementation for six weeks reduced diabetic neuropathy pain. The benefits were clearer in subjects who consumed 600 mg of benfotiamine daily compared with those who took 300 mg, and in those who took benfotiamine for a longer period of time (Stracke 2008).
In a clinical trial in 13 subjects with type 2 diabetes, participants consumed a high-AGE meal before and after a 3-day course of benfotiamine, 1050 mg per day. The subjects’ vascular and endothelial function were assessed after both high-AGE meals. Signs of vascular dysfunction were completely prevented by benfotiamine administration, and biomarkers of endothelial dysfunction and oxidative stress were significantly reduced (Stirban 2006).
Clinical and animal studies have demonstrated the efficacy of benfotiamine in the treatment of diabetes-related neuropathy, kidney disease, peripheral vascular disease, and retinopathy (Stirban 2006; Chakrabarti 2011; Stracke 1996; Simeonov 1997; Winkler 1999; Haupt 2005; Nikolic 2009).
Carnosine. The peptide carnosine is capable of inhibiting formation of AGEs and even reversing protein glycation (Boldyrev 2013; Seidler 2004). In a study on diabetic mice, carnosine supplementation increased plasma levels of carnosine 20-fold, reduced triglyceride levels by 23%, and increased stability of atherosclerotic lesions (Brown 2014). Carnosine has also been shown to improve the ability of cells to survive in the presence of high glucose concentrations, and improve wound healing in diabetic animals (Ansurudeen 2012). An animal model of diabetes showed carnosine supplementation improved the ability of red blood cells to change their shape as necessitated by mechanical forces encountered during blood flow; this process is impaired in diabetes, contributing to diabetic complications (Yapislar 2012).
Pyridoxal 5’-phosphate. Pyridoxal 5’-phosphate is the active form of vitamin B6 and an effective anti-glycation agent (Nakamura 2007; di Salvo 2012). Treating 20 type 2 diabetics with 35 mg pyridoxal 5’-phosphate along with 3 mg activated folate and 2 mg vitamin B12 improved skin sensation in diabetic peripheral neuropathy (Walker 2010). Supplementation with pyridoxal 5’-phosphate significantly decreased high concentrations of glycation-induced toxic compounds in diabetic rats, and prevented the progression of diabetic neuropathy (Higuchi 2006; Nakamura 2007).
In addition to preventing protein glycation, pyridoxal 5’-phophate is one of the most effective inhibitors of lipid (fat) glycation. Lipid AGEs are elevated in diabetic patients compared with healthy controls, and accumulation of lipid AGEs contributes to vascular diseases related to diabetes and aging (Miyazawa 2012; Bucala 1993).
Phytochemical AMPK Activators
AMPK (adenosine monophosphate-activated protein kinase) is a critical energy sensor in the body. Activation of AMPK helps regulate energy metabolism, increasing fat burning and glucose utilization while blocking fat and cholesterol synthesis (Coughlan 2014; Park, Huh 2014). AMPK activation is a mechanism by which the preeminent antidiabetic drug metformin exerts some of its well-known metabolic benefits (Choi 2013; Yue 2014).
Gynostemma pentaphyllum. Gynostemma pentaphyllum (G. pentaphyllum) is a climbing vine of the family Cucurbitaceae (cucumber or gourd family) that is native to Asian countries including Korea, China, and Japan, where it is used as tea and in traditional medicine. Like metformin, gynostemma extract activates AMPK (Park, Huh 2014).
In animal and human cell cultures, extracts from G. pentaphyllum have been shown to improve insulin sensitivity, reduce levels of glucose and cholesterol, enhance immune function, and inhibit cancer growth (Lu 2008; Yeo 2008; Megalli 2006; Liu, Zhang, 2014). In a randomized controlled trial, an extract from gynostemma modestly reduced body weight and fat mass in obese subjects (Park, Huh 2014). Results from another trial found gynostemma tea improved insulin sensitivity, and lowered fasting glucose nearly ten times more than placebo (Huyen 2013).
In a clinical trial involving 25 diabetics, a gynostemma extract was tested as add-on therapy to the sulfonylurea drug gliclazide. Reductions in plasma glucose and HbA1C were nearly three times greater in the gynostemma extract group compared with placebo. Gynostemma acted by increasing insulin sensitivity rather than stimulating insulin release. It also prevented weight gain and hypoglycemia, which are often associated with sulfonylurea drugs (Huyen 2012).
In a trial in participants with non-alcoholic fatty liver disease, a condition strongly linked to insulin resistance, treatment with gynostemma extract, as an adjunct to diet, resulted in a significant reduction in liver enzymes and insulin levels, a decrease in body mass index, and increased insulin sensitivity (Chou 2006; Utzschneider 2006).
Hesperidin. Hesperidin and related flavonoids are found in a variety of plants, but especially in citrus fruits, particularly their peels (Umeno 2016; Devi 2015). Digestion of hesperidin produces a compound called hesperetin along with other metabolites. These compounds are powerful free radical scavengers and have demonstrated anti-inflammatory, insulin-sensitizing, and lipid-lowering activity (Li 2017; Roohbakhsh 2014). Findings from animal and in vitro research suggest hesperidin’s positive effects on blood glucose and lipid levels may be related in part to activation of the AMP-activated protein kinase (AMPK) pathway (Jia 2015; Rizza 2011; Zhang 2012). Accumulating evidence suggest hesperidin may help prevent and treat a number of chronic diseases associated with aging (Li 2017).
Hesperidin may protect against diabetes and its complications, partly through activation of the AMPK signaling pathway. Coincidentally, metformin, a leading diabetes medication, also activates the AMPK pathway. In a six-week randomized controlled trial on 24 diabetic participants, supplementation with 500 mg of hesperidin per day improved glycemic control, increased total antioxidant capacity, and reduced oxidative stress and DNA injury (Homayouni 2017). Using urinary hesperetin as a marker of dietary hesperidin, another group of researchers found those with the highest level of hesperidin intake had 32% lower risk of developing diabetes over 4.6 years compared to those with the lowest intake level (Sun 2015).
In a randomized controlled trial, 24 adults with metabolic syndrome were treated with 500 mg of hesperidin per day or placebo for three weeks. After a washout period, the trial was repeated with hesperidin and placebo assignments reversed. Hesperidin treatment improved endothelial function, suggesting this may be one important mechanism behind its benefit to the cardiovascular system. Hesperidin supplementation also led to a 33% reduction in median levels of the inflammatory marker high-sensitivity C-reactive protein (hs-CRP), as well as significant decreases in levels of total cholesterol, apolipoprotein B (apoB), and markers of vascular inflammation, relative to placebo (Rizza 2011). In another randomized controlled trial in overweight adults with evidence of pre-existing vascular dysfunction, 450 mg per day of a hesperidin supplement for six weeks resulted in lower blood pressure and a decrease in markers of vascular inflammation (Salden 2016). Another controlled clinical trial included 75 heart attack patients who were randomly assigned to receive 600 mg hesperidin per day or placebo for four weeks. Those taking hesperidin had significant improvements in levels of high-density lipoprotein (HDL) cholesterol and markers of vascular inflammation and fatty acid and glucose metabolism (Haidari 2015).
Green tea extract. Green tea extract, a major constituent of which is epigallocatechin-3-gallate (EGCG), has been shown to reduce glucose and insulin levels and improve insulin sensitivity. In a rodent model of accelerated aging, EGCG supplementation lowered glucose and insulin levels. EGCG also increased insulin sensitivity, decreased liver fat accumulation, and improved markers of mitochondrial function (Liu, Chan 2015). In animal models of diabetes, green tea has been shown to protect against diabetic retinopathy (Silva 2013; Kumar 2012).
In a 16-week randomized controlled trial in 92 subjects with type 2 diabetes and blood lipid abnormalities, participants took 500 mg green tea extract three times daily. The green tea group showed significant increases in insulin sensitivity and HDL cholesterol levels, as well as a significant decrease in serum triglycerides (Liu, Huang, 2014). A two-month trial in 103 healthy postmenopausal women found a significant difference in glucose and insulin levels between a group that took up to 800 mg EGCG per day and a placebo group. Glucose and insulin levels fell in the EGCG group, but rose in the placebo group (Wu 2012). At the end of a four-week trial of catechin-rich green tea in 22 postmenopausal women, those in the green tea group had significantly lower postprandial glucose and significantly better after-meal oxidative stress parameters (Takahashi 2014).
Elevated blood pressure is one of the characteristic cardiovascular risk factors often found in diabetics and prediabetics. A randomized controlled trial administered daily a green tea extract powder containing a total of 544 mg polyphenols to 60 prediabetic subjects. This led to significantly reduced HbA1C and diastolic blood pressure (Fukino 2008). Similarly, a trial in overweight or obese middle-aged men found 800 mg EGCG daily significantly reduced diastolic blood pressure (Brown 2009).
Among additional possible mechanisms underlying green tea’s benefits are suppression of inflammatory genes and mitigation of oxidative damage (Uchiyama 2013; Jang 2013; Yang 2013). Also, green tea, black tea (a rich source of theaflavin polyphenols), and oolong tea have been reported to inhibit the alpha-glucosidase enzyme, causing less carbohydrate to be digested and absorbed (Satoh 2015; Yang 2015; Oh 2015). Other evidence suggests green tea constituents may activate AMPK (Liu, Chan 2015).
Bilberry extract. Closely related to blueberry, bilberry is rich in polyphenols and anthocyanins. In a study in diabetic mice, a bilberry extract reduced blood glucose and enhanced insulin sensitivity by activating AMPK (Ogawa 2014; Takikawa 2010). Bilberry polyphenols also have potent anti-inflammatory and free radical-scavenging actions (Subash 2014; Kolehmainen 2012). Bilberry has also been shown in animal studies to combat diabetic retinopathy (Kim, Kim 2015); and a clinical study in 180 type 2 diabetics showed that bilberry, in combination with several other micronutrients, improved measures of ocular health and visual acuity in subjects with preclinical or early diabetic retinopathy (Moshetova 2015).
In a preliminary controlled trial in eight type 2 diabetic males, a concentrated bilberry extract significantly lowered after-meal glucose and insulin levels compared with placebo. Reduced rates of carbohydrate digestion and absorption likely accounted for these effects. Specifically, bilberry polyphenols may have inhibited the action of alpha-glucosidase, preventing the breakdown of carbohydrates into glucose (Hoggard 2013).
Prevention of Exaggerated Post-Meal Blood Glucose Elevations
Several natural compounds can help prevent post-meal surges in blood glucose. These postprandial glucose spikes increase the risk of cardiometabolic diseases not only for diabetics and prediabetics, but also for people whose fasting glucose level is in the conventional “normal” range. Among the mechanisms that natural substances target to allow tighter control of post-meal glucose levels are alpha-glucosidase inhibition, alpha-amylase inhibition, SGLT1 inhibition, and sucrase inhibition (Van de Laar 2005; Matsuo 1992; Melzig 2007; Kinne 2011; Lee 1982).
Alpha-glucosidase inhibition. The alpha-glucosidase enzymes in the intestine break down carbohydrates into simple sugars so they can be absorbed. Inhibiting alpha-glucosidase reduces the amount of simple sugars available for absorption, mitigating postprandial glucose surges (Tundis 2010).
White mulberry leaf extract. White mulberry leaf has a long history of use in traditional Chinese medicine for preventing and treating diabetes (Mudra 2007). A component of white mulberry, called 1-deoxynojirimycin, impedes the action of alpha-glucosidase, slowing carbohydrate absorption and preventing post-meal blood sugar spikes (Banu 2015; Naowaboot 2012; Nakanishi 2011). This effect of the white mulberry leaf extract has been demonstrated in healthy subjects, type 2 diabetics, and those with impaired glucose tolerance (Asai 2011; Banu 2015; Mudra 2007).
A 4-week randomized controlled trial in 36 subjects with impaired fasting glucose found white mulberry leaf extract significantly reduced post-meal glucose and insulin levels (Kim, Ok 2015). A trial in 24 subjects with type 2 diabetes compared a white mulberry leaf product to the sulfonylurea drug glyburide. White mulberry decreased total cholesterol by 12%, LDL cholesterol by 23%, and triglycerides by 16%; raised HDL cholesterol by 18%; and reduced fasting blood glucose and oxidative stress markers. Glyburide only slightly improved glycemic control and triglycerides (Andallu 2001). A clinical study in healthy volunteers found that 1-deoxynojirimycin-enriched white mulberry powder suppressed post-prandial blood glucose surge and lowered insulin levels (Kimura 2007).
Specially roasted coffee and green coffee bean extract. Epidemiologic studies have linked coffee consumption with reduced risk of type 2 diabetes, Alzheimer disease, Parkinson disease, and certain cancers. This association may be explained by the chlorogenic acid content of coffee (Song 2014; Ong 2012; Meng, Cao 2013). Chlorogenic acid, a polyphenol, has demonstrated multiple mechanisms through which it exerts antidiabetic activity, including inhibition of alpha-glucosidase and the glucose-elevating liver enzyme glucose-6-phosphatase, oxidative stress modulation, insulin sensitization, and AMPK activation (Bassoli 2008; Ishikawa 2007; Rodriguez de Sotillo 2006; Simsek 2015; Henry-Vitrac 2010; Andrade-Cetto 2010). Chlorogenic acid also lowers levels of blood lipids (Meng, Cao 2013). Chlorogenic acid’s inhibition of alpha-glucosidase allows it to delay glucose absorption, which can result in a more gradual rise in postprandial glucose levels (Johnston 2003).
In a clinical trial in 42 individuals with type 2 diabetes, 300 mg of a chlorogenic acid-containing plant extract daily for four weeks significantly reduced fasting plasma glucose, C-reactive protein (CRP), and liver enzymes compared with placebo (Abidov 2006). In another trial, a single dose of coffee polyphenols during a glucose-loading test in healthy individuals significantly protected endothelial function (Ochiai 2014). In a mouse study, green coffee bean extract, a rich source of chlorogenic acid, significantly reduced visceral fat accumulation and improved insulin sensitivity, effects that may have been due to suppression of genes associated with fat deposition and inflammation (Song 2014).
Raw green coffee beans are rich in chlorogenic acid (Farah 2008). However, the conventional coffee roasting process appears to significantly reduce the chlorogenic acid content of brewed coffee (Moon 2009; Zapp 2013). Although several studies have shown conventional coffee has meaningful health benefits, consuming a coffee high in chlorogenic acid may extend these benefits further (Johnston 2003; Hemmerle 1997). Fortunately, scientists have developed a method for roasting coffee that yields brewed coffee with higher-than-typical chlorogenic acid content (Zapp 2013). Individuals who wish to attain the most benefit from coffee polyphenols should consume coffee specially prepared to ensure that chlorogenic acid is retained during the roasting process.
Brown seaweed extract. Metabolic syndrome prevalence is lower in some Asian countries than in other parts of the world, and some researchers suspect dietary brown seaweed may be protecting these populations (Teas 2009). In laboratory experiments, brown seaweed extracts from Ascophyllum nodosum and Fucus vesiculosus inhibited alpha-glucosidase and alpha amylase enzymes (Roy 2011).
In a randomized controlled trial in 23 healthy subjects, a single 500-mg dose of brown seaweed extract caused a 48.3% decrease in post-meal blood sugar spikes. Significant reductions in post-meal insulin concentrations and improved insulin sensitivity were also observed (Paradis 2011).
In a study in diabetic mice, polyphenolic fractions prepared from brown seaweed extract were shown to improve fasting serum glucose levels and blunt the rise in blood glucose following an oral sugar challenge. Compared with untreated mice, the mice given the polyphenol extract exhibited decreased total blood cholesterol. The seaweed-derived polyphenols also restored liver glycogen (stored carbohydrate) content (Zhang 2007).
Alpha-amylase inhibition. Like alpha-glucosidase, alpha-amylase is an enzyme that breaks down larger sugars and starches into smaller molecules that can be rapidly absorbed. Inhibition of alpha-amylase is another way to reduce the rate of sugar absorption (Tundis 2010).
- Sorghum extract. Grain sorghum (Sorghum bicolor) is cultivated for animal and human consumption in several parts of the world, especially Africa, Asia, and Latin America. The grain’s unique protein and starch composition reduce its digestibility and cause it to slow glucose absorption (Poquette 2014). Also, in animal models of diabetes, sorghum inhibited glucose production in the liver (gluconeogenesis) and improved insulin sensitivity. In a laboratory experiment, a flavonoid- and proanthocyanidin-rich sorghum extract inhibited the alpha-amylase enzymes that convert starch into sugars. In a randomized trial in 10 healthy men, muffins made with sorghum were shown to reduce average after-meal glucose and insulin responses (Hargrove 2011; Poquette 2014; Kim 2012; Park 2012).
Additional mechanisms. Some natural products suppress postprandial hyperglycemia via other mechanisms, including inhibition of glucose transporters or sucrase, an enzyme that facilitates digestion and absorption of sucrose (table sugar).
- Phloridzin. Phloridzin is a unique polyphenol found in high concentrations in apples and apple trees. This compound appears to suppress glucose absorption in the intestine by inhibiting sugar transporter systems in the intestine (SGLT1) and kidney (SGLT2). As a result, glucose reabsorption in the kidney is reduced and glucose excretion into the urine is promoted. The oral diabetes medication canagliflozin (Invokana) is also based on this mechanism (Sarnoski-Brocavich 2013; Najafian 2012; Masumoto 2009).
- L-arabinose. L-arabinose is a poorly-absorbed five-carbon sugar found in the cell walls of many plants. L-arabinose inhibits the activity of sucrase, which is an intestinal enzyme that breaks down sucrose (table sugar) into the absorbable sugars glucose and fructose. When l-arabinose is consumed in combination with sucrose, the breakdown of sucrose is delayed, so that glucose is absorbed more slowly, which results in less exaggerated blood glucose and insulin responses. L-arabinose in combination with chromium, a natural insulin sensitizer, significantly lowered circulating glucose and insulin levels in nondiabetic subjects who underwent an oral sucrose challenge (Karley 2005; Kaats 2011; Krog-Mikkelsen 2011).
Maqui berry extract. Maqui berries (Aristotelia chilensis) are a purple-black fruit native to Chile that have garnered attention for their strong capacity to quench free radicals. They are also the richest known source of highly active polyphenolic compounds called delphinidins. When compared with other berries such as cranberries, blueberries, raspberries, and blackberries, maqui berries were found to be at least three times higher in total polyphenols and to have approximately three times greater free radical-quenching capacity (Watson 2015).
In a 2014 study to investigate its effects on blood glucose control, a single 200 mg dose of a standardized maqui berry extract 30 minutes prior to ingesting a serving of white rice was found to delay and decrease the rising levels of blood glucose and insulin better than placebo in 10 volunteers with moderate glucose intolerance (Hidalgo 2014). Similarly, single doses of 60 mg, 120 mg, and 180 mg taken one hour before oral glucose tolerance testing effectively improved fasting blood glucose levels as well as glucose and insulin responses in pre-diabetic individuals, with 180 mg having the greatest impact on blood glucose levels (Alvarado, Leschot 2016). To assess its long-term effects, a group of 31 moderately glucose-intolerant subjects were treated with 180 mg standardized maqui berry extract daily for three months. Result showed progressive decreases in HbA1c values at 30, 60, and 90 days. In addition, LDL-cholesterol levels were lower and HDL-cholesterol levels were higher at the end of the trial, indicating improved lipid metabolism (Alvarado, Schoenlau 2016).
Several mechanisms may contribute to the positive effects of maqui berries on glucose regulation. Findings from preclinical research suggest maqui berry extract may decrease glucose production in the liver and increase insulin sensitivity (Rojo 2012). In an animal model of diabetes, maqui berry extract reduced intestinal absorption of glucose (Hidalgo 2014). Other research has indicated that maqui berry extract inhibits the inflammatory signaling between fat cells and immune cells that is associated with the development of insulin resistance (Reyes-Farias 2015).
Clove bud extract. Clove (Syzygium aromaticum), a well-known spice, has shown potential to improve glucose levels and aid in overall metabolism (Tu 2014; Kuroda 2012). An ethanol extract of clove flower buds was found to decrease blood glucose levels in diabetic mice (Kuroda 2012); in diabetic and lipid-disordered mice, supplementation with an alcohol clove extract resulted in lower glucose, triglyceride, free fatty acid, HbA1C levels (Sanae 2014). Its positive effects on metabolism were further demonstrated in an animal model of obesity, in which treatment with an alcohol extract of clove reduced the negative impact of a high-fat diet on body weight as well as lipid, glucose, and insulin levels (Jung 2012).
Findings from a clinical study on human subjects, which are not yet published, add more support for the potential anti-diabetic effects of clove. After 30 days of supplementation with 250 mg per day of a water extract of clove, participants had lower after-meal blood glucose levels. Furthermore, participants with higher blood glucose levels before the trial experienced greater reductions in after-meal glucose levels (AKAY 2017).
In vitro research has shown that a clove extract has insulin-like effects on liver cells, inhibiting the breakdown of stored carbohydrates into glucose and preventing a subsequent rise in levels of circulating glucose (Prasad 2005; Sanae 2014). In muscle cells, clove extract stimulated the conversion of glucose into energy and enhanced mitochondrial function (Tu 2014). Some individual compounds from an ethanol extract of clove have been found to activate cellular pathways that increase glucose and lipid uptake (Kuroda 2012).
Chromium. Chromium, a trace mineral, is essential for carbohydrate and fat metabolism, and is believed to act as an insulin-sensitizing agent. Chromium deficiency has been associated with insulin resistance and diabetes (Suksomboon 2014; Anderson 1997). A 2014 study found chromium deficiency was common in people with prediabetes. The authors recommended screening for chromium deficiency in both prediabetics and diabetics, and supplementing if a deficiency was identified (Rafiei 2014).
Evidence suggests chromium supplementation may improve control of blood glucose, raise HDL cholesterol, and lower triglycerides in type 2 diabetes. Chromium has also been shown to significantly lower HbA1C in type 2 diabetics (Suksomboon 2014; Rabinovitz 2004).
Cinnamon. The culinary spice cinnamon has been shown to promote healthy glucose metabolism and improve insulin sensitivity (Anderson 2013; Couturier 2010; Sartorius 2014; Ranasinghe 2012). Studies that supplemented type 2 diabetics and healthy individuals with 1‒6 g of cinnamon reported lower levels of fasting glucose, HbA1C and after-meal glucose and insulin concentrations, as well as improvements in insulin sensitivity. These effects have been demonstrated even in those already taking glucose-lowering medication (Lu 2012; Davis 2011; Magistrelli 2012; Hoehn 2012).
In a study in type 2 diabetics, a water-soluble cinnamon extract given at a dosage of 360 mg daily lowered HbA1C from 8.9% to 8.0%. The antidiabetic effects of cinnamon extracts have been attributed in part to activation of peroxisome proliferator-activated receptors, key regulators of glucose and fat metabolism (Sheng 2008; Lu 2012; Ferre’ 2004).
Several polyphenol compounds in cinnamon have free-radical-scavenging properties. In a rodent study, a specific cinnamon polyphenol, procyanidin B2, was shown to delay the formation of advanced glycation end products (AGEs) and diabetic cataracts (Muthenna 2013; Jayaprakasha 2006).
Omega-3 fatty acids. Omega-3 fats are healthy fats found in fish and some nuts, seeds, vegetables, and algae (Higdon 2014). Diets rich in omega-3 fatty acids have been shown to promote weight loss, enhance insulin sensitivity, and reduce death from cardiovascular disease by reducing inflammation, improving lipid profiles, and reducing blood clotting. When omega-3 fats are incorporated into cell membranes, they make the cell surface more fluid and pliable and appear to enhance cells’ ability to remove glucose from the bloodstream (McEwen 2010; Udupa 2013; Albert 2014; Franekova 2015). A large study in older adults demonstrated individuals with the highest blood concentrations of omega-3 fats, compared with the lowest, had up to 43% lower risk of diabetes (Djousse 2011).
In a randomized controlled trial in overweight type 2 diabetic patients, supplementation with the omega-3 fatty acid eicosapentaenoic acid (EPA) significantly decreased serum insulin, fasting glucose, HbA1C, and insulin resistance (Sarbolouki 2013). Another trial of supplementation with 2.3 g of the omega-3 fats EPA and docosahexaenoic acid (DHA) in 84 subjects with type 2 diabetes found a significant reduction in serum inflammatory biomarkers (Malekshahi Moghadam 2012). An eight-week trial in individuals with metabolic syndrome or early type 2 diabetes found fish oil lowered triglycerides and HbA1C and raised HDL cholesterol (Lee, Ivester 2014). Another trial in 44 type 2 diabetics found omega-3 supplementation for 10 weeks improved insulin sensitivity (Farsi 2014).
A randomized placebo-controlled trial tested a combination of EPA, DHA, and the plant-sourced omega-3 fatty acid alpha-linolenic acid in over 1000 diabetics with a history of heart attack. Subjects receiving the omega-3 preparation had 84% lower risk of a ventricular arrhythmic event, and 72% lower risk of a combined outcome of fatal heart attacks and ventricular arrhythmic events (Kromhout 2011).
Omega-3 fatty acids from fish oil, DHA and EPA, appear to protect against some of the changes in blood vessel function associated with post-meal blood sugar surges. A six-week trial in 34 subjects with type 2 diabetes found omega-3 fatty acid supplementation significantly protected against post-meal dysfunction in small and large blood vessels (Stirban 2010).
A review found greater consumption of omega-3 fats from fish was associated with a 15‒19% lower rate of death from cardiovascular disease, as well as lower triglycerides, decreased inflammation, lower blood pressure, and diminished platelet activation and aggregation (McEwen 2010).
Magnesium. Magnesium is involved in more than 300 metabolic reactions and plays a key role in carbohydrate metabolism. Magnesium participates in insulin secretion and function, and low magnesium levels are correlated with insulin resistance (Gums 2004; Bertinato 2015; Paolisso 1990). Low magnesium levels are significantly more common in people with diabetes and impaired glucose tolerance compared with the general population, and higher magnesium levels correlate with lower HbA1C (Hata 2013; Hruby 2014; Hyassat 2014; Galli-Tsinopoulou 2014; Azad 2014). Higher magnesium intake is associated with decreased risk of developing type 2 diabetes (Guerrero-Romero 2014).
Magnesium supplementation has been shown to lower blood levels of glucose and lipids, as well as blood pressure, in type 2 diabetics. Magnesium supplements were also found to lower highly-sensitive C-reactive protein (hs-CRP), a marker of inflammation, in prediabetics with low serum magnesium (Solati 2014; Simental-Mendia 2014).
Magnesium plays a critical role in cardiovascular health. A study in over 13 000 US adults found women with the highest serum magnesium levels had a 56% lower risk of coronary artery disease compared with those with the lowest levels; in men, those with the highest serum magnesium had a 27% less risk compared with those whose levels were lowest. Similarly, women with the lowest dietary magnesium intake had a more than 1.3-fold greater risk of cardiovascular disease (Kolte 2014). One study found that, in diabetic patients with coronary artery or peripheral vascular disease, there was a significant correlation between low magnesium and high fasting plasma glucose and HbA1C (Agrawal 2011).
Oxidative Stress Inhibitors and Anti-Inflammatory Agents
Coenzyme Q10. Coenzyme Q10 (CoQ10) is essential to mitochondrial energy metabolism, and a powerful inhibitor of oxidative stress (Littarru 2007). CoQ10 deficiency has been associated with diabetes (Amin 2014; Kolahdouz 2013; Eriksson 1999). In a randomized controlled trial in 64 type 2 diabetic patients, supplementation with 200 mg CoQ10 per day for 12 weeks decreased serum HbA1C concentration and lowered levels of total and LDL cholesterol (Kolahdouz 2013). A clinical trial in 74 type 2 diabetic subjects found 100 mg CoQ10 twice daily resulted in significantly decreased HbA1C and blood pressure (Hodgson 2002). In a placebo-controlled trial in 23 statin-treated type 2 diabetics, 200 mg CoQ10 per day significantly improved a marker of vascular endothelial dysfunction (Hamilton 2009; Watts 2002).
In an animal model of diabetes, CoQ10 treatment significantly improved insulin resistance, reduced serum levels of insulin and glucose, and increased levels of the energy-regulating hormone adiponectin six-fold (Amin 2014). High levels of adiponectin have been linked to decreased risk of diabetes and cardiovascular complications (Lindberg 2015; Zoico 2004; Yamamoto 2014).
Long-term use of CoQ10 was demonstrated in two animal studies to be protective against progressive diabetic neuropathy. The beneficial effects of CoQ10 may have been attributable to reduction of oxidative damage and inflammation, both key factors implicated in diabetic neuropathy (Zhang, Eber 2013; Shi 2013).
The reduced form of CoQ10—ubiquinol— is absorbed more efficiently than the ubiquinone form (Langsjoen 2008; Hosoe 2007).
Curcumin. Curcumin is a major active component of turmeric, the spice derived from the plant Curcuma longa. Turmeric has been used as a treatment for diabetes in Ayurvedic and traditional Chinese medicine for centuries. Curcumin’s primary mechanisms of action are its ability to neutralize reactive free radicals and reduce inflammation (Nabavi 2015; Zhang, Fu 2013; Meng, Li 2013).
A randomized controlled trial in 240 prediabetic subjects showed curcumin supplementation significantly lowered risk of progressing from prediabetes to type 2 diabetes. During the nine-month trial, none of the prediabetic subjects treated with curcumin progressed to diabetes, whereas over 16% of subjects in the control group were diagnosed with type 2 diabetes. By the end of the study, subjects in the curcumin group had significantly greater insulin sensitivity and beta-cell function, as well as higher adiponectin levels than the placebo group (Chuengsamarn 2012).
Additional experimental studies and human trials indicate curcumin is a promising natural agent for the prevention and treatment of diabetes and its complications. Curcumin appears to increase insulin sensitivity and reduce blood levels of glucose and lipids. It also may protect insulin-producing beta cells in the pancreas (Nabavi 2015; Zhang, Fu 2013).
Most curcumin formulations have relatively poor bioavailability, requiring high doses to achieve desired blood levels. Fortunately, a novel curcumin formulation, BCM-95, has been developed that delivers up to seven times more bioactive curcumin to the blood than earlier curcumin products (Antony 2008).
Resveratrol. Resveratrol, a polyphenol that has received widespread attention for its anti-aging effects, holds promise in type 2 diabetes (Hausenblas 2015; Bruckbauer 2013; Fiori 2013; Tome’-Carneiro 2013; Mozafari 2015). A rigorous review of randomized controlled trials found resveratrol improved systolic blood pressure, HbA1C, and creatinine when used as an adjunct to drug treatment in type 2 diabetes (Hausenblas 2015). In one of these studies, supplementation with resveratrol at 1 g per day for 45 days resulted in a significant decrease in fasting glucose, insulin, and HbA1C and an increase in insulin sensitivity and HDL cholesterol levels. Notably, the improvements in HbA1C and HDL cholesterol were comparable to those achieved by leading antidiabetic drugs (Movahed 2013).
Lipoic acid. Lipoic acid is a free radical scavenger made by the body in small quantities, though levels decline significantly with age (Park, Karuna 2014; Higdon 2012). Lipoic acid may support healthy blood glucose control by activating AMPK, protecting pancreatic beta cells, and augmenting glucose removal from the bloodstream. Lipoic acid has been used for the prevention and treatment of diabetic neuropathy in Germany for several decades (Ziegler 1999; Gomes 2014; Golbidi 2011; Ibrahimpasic 2013).
In a study in subjects with impaired glucose tolerance, arterial flow (a measure of endothelial function) was markedly decreased during fasting and after a glucose challenge. Intravenous administration of 300 mg lipoic acid before the glucose challenge prevented the endothelial dysfunction induced by high blood glucose. Lipoic acid decreases oxygen free radicals, which in excess promote endothelial dysfunction and contribute to diabetes, high blood pressure, and cardiovascular disease (Xiang 2008; Park, Karuna 2014; Gomes 2014).
Lipoic acid comes in two “mirror image” forms labeled “R” and “S.” The R form is the active form produced and used in living systems (Gomes 2014). Inexpensive chemical manufacturing produces equal quantities of R and S lipoic acid, often labeled “R/S lipoic acid” or simply “alpha-lipoic acid” (Flora 2009). Newer precision techniques allow production of a pure, more stable R-lipoic acid supplement, delivering the most bioavailable form. This form is known as sodium R-lipoate, or Na-RALA.
A dose of pure R-lipoic acid provides twice the active ingredient compared with typical alpha-lipoic acid supplements, simply because the whole dose consists of the active “R” molecule. Look for the “R” label to ensure you are getting the most potent form of lipoic acid (Smith 2005; Streeper 1997).
Blueberry extract. Blueberries are a concentrated source of polyphenols and anthocyanins that have multiple antidiabetic effects, including protection of pancreatic beta cells, anti-inflammatory properties, and free-radical-scavenging abilities (Liu, Gao 2015; Martineau 2006; Abidov 2006).
A four-week randomized controlled trial of blueberry supplementation was conducted in 32 obese, insulin-resistant adults without diabetes. Subjects were given 45 g of freeze-dried blueberry powder—the equivalent of two cups of whole blueberries—daily for six weeks. Compared with placebo, blueberry treatment significantly improved insulin sensitivity (Stull 2010).
In a study in rodents fed a high-fructose diet, fasting insulin was elevated, and insulin sensitivity and pancreatic beta-cell function declined. However, when the diet was supplemented with blueberries, these changes were minimized; and when a larger percentage of the diet was derived from blueberries, the effect was greater. Cholesterol and abdominal fat also decreased in the blueberry-fed animals (Khanal 2012).
In a rodent model of diet-induced inflammation similar to that observed in diabetes, the addition of blueberry powder to the animals’ diet prevented inflammatory changes, and protected the mice from developing insulin resistance and high blood sugar (DeFuria 2009). Soybean flour enriched with a concentrate of blueberry polyphenols was shown to reduce hyperglycemia, weight gain, and serum cholesterol in mice. The blueberry-fortified flour also reduced glucose production in the liver by 24‒74% (Roopchand 2013).
In cell culture studies, an anthocyanin-rich blueberry extract exhibited insulin-sensitizing properties, conferred protection against glucose and fatty acid toxicity, and enhanced proliferation of insulin-producing pancreatic beta cells (Martineau 2006; Liu, Gao 2015).
Grape polyphenols. Grapes are a source of polyphenols, proanthocyanidins, and resveratrol, all of which modulate oxidative stress and have been studied in a wide range of health conditions, including high blood pressure, cancer, and Alzheimer disease (Pasinetti 2014; Kaur 2009; Feringa 2011). Grape polyphenols appear to have important antidiabetic effects and protect tissues from the damaging effects of blood sugar elevations.
In a four-week, randomized, placebo-controlled trial in 32 type 2 diabetics, consumption of 600 mg per day of grape seed extract significantly lowered fructosamine compared with placebo. Fructosamine is a test similar to HbA1C that measures blood sugar level over several weeks. Grape seed extract also lowered total cholesterol and hs-CRP, and significantly elevated blood glutathione, one of the body’s primary internal antioxidants (Kar 2009). Another trial found the non-alcoholic portion of red wine, which is rich in grape polyphenols, increased insulin sensitivity and reduced cardiovascular risk (Chiva-Blanch 2013).
A randomized controlled trial administered 2 g of grape polyphenols per day to healthy but overweight first-degree relatives of type 2 diabetics for eight weeks. Subjects were then challenged with substantial doses of fructose, the sugar present in fruit juices and many sweetened beverages. In the placebo group, the fructose challenge resulted in increased oxidative stress and decreased insulin sensitivity and mitochondrial activity. All of these negative effects were prevented in the polyphenol group (Hokayem 2013).
Gamma tocopherol. After-meal blood sugar surges can injure the lining of blood vessels, causing endothelial dysfunction and vascular disease. Gamma tocopherol is a form of vitamin E with both anti-inflammatory and free-radical-scavenging activity. Two trials in healthy men found gamma tocopherol supplementation protected against changes associated with endothelial dysfunction induced by after-meal glucose spikes (Mah, Noh 2013; Masterjohn 2012; Mah, Pei 2013).
Ginkgo biloba. A randomized controlled trial tested the effects of adding Ginkgo biloba to metformin therapy in patients with metabolic syndrome. Forty participants received—in addition to their ongoing metformin treatment—either a Ginkgo biloba extract, administered in a single daily dose as a 120 mg capsule, or a placebo, for 90 days. At completion, participants who received the extract had significant decreases in HbA1c (8%), fasting serum glucose (12%), insulin levels (44%), insulin resistance (19%), body mass index (7%), abdominal body fat (23%), and serum leptin (43%) compared with their levels at the beginning of the study. Several inflammatory markers also showed decreases, including high-sensitivity C-reactive protein (20%), TNF-alpha (48%), and IL-6 (37%). These benefits were not seen in the placebo group. The combination of metformin and Ginkgo biloba extract did not lead to any observable adverse effects during the course of study (Aziz, Hussain, Mahwi, Ahmed 2018).
Another randomized controlled trial showed similar benefits. In the trial, patients with type 2 diabetes, which was poorly controlled with metformin, received Ginkgo biloba extract supplementation. After 90 days, participants who received the extract had decreased blood levels of HbA1c (10.5%), fasting serum glucose (20%), and insulin (28%); and reduced BMI (7%), waist circumference (3%), and abdominal fat (17%) (Aziz, Hussain, Mahwi, Ahmed, Rahman 2018). Previously, a double-blind clinical trial reported that the co-ingestion of 120 mg of a Ginkgo biloba extract together with 500 mg metformin did not significantly change the metabolism of metformin in healthy individuals or in individuals with type 2 diabetes mellitus (Kudolo 2006).
Vitamin D. Vitamin D deficiency has been associated with both diabetes and obesity, and evidence suggests vitamin D status is closely related to glucose metabolism. People with low vitamin D were more likely to have diabetes, independent of their body weight (Clemente-Postigo 2015).
Several mechanisms have been suggested to account for the association between vitamin D levels and poor blood glucose control. Through its role in calcium regulation, vitamin D may improve insulin sensitivity and regulate pancreatic beta cell function. Vitamin D may also modulate systemic inflammation, which is associated with insulin resistance and type 2 diabetes. Finally, vitamin D may directly stimulate production of insulin receptors in target tissues and thus enhance glucose clearance from the blood (Clemente-Postigo 2015; Pittas 2007). An optimal target range for vitamin D blood levels is between 50 and 80 ng/mL.
Folate. In type 2 diabetes, elevated plasma homocysteine is strongly linked to increased risk of cardiovascular disease and death. Homocysteine promotes endothelial dysfunction through a number of different mechanisms. The B vitamin folate, in concert with vitamin B12, lowers homocysteine by converting it back to the amino acid methionine. Both low folate intake and low blood folate levels are strongly associated with high plasma homocysteine (Selhub 2000; Moat 2004; Sudchada 2012; Van Guelpen 2009; Miller 2003; de Bree 2001; Koehler 2001).
A thorough review and analysis of randomized controlled trials assessed the effect of folic acid supplementation on homocysteine levels in type 2 diabetics. In this population, 5 mg per day of folic acid significantly decreased homocysteine levels, to a degree believed to lower the risk of cardiovascular disease, and improved glycemic control (Sudchada 2012).
Genetic predisposition to inefficient conversion of folic acid into the metabolically active 5-methyltetrahydrofolate (5-MTHF) is common (Huo 2015). Supplementation with L-methylfolate (instead of folic acid) avoids this potential problem and is preferable to folic acid.
Irvingia gabonensis. Also known as African mango, Irvingia gabonensis is an African tree that bears mango-like fruit (MMSCC 2015). An extract of irvingia seed has been shown to lower blood glucose and lipid levels, and reduce excess body weight (Ross 2011; Ngondi 2009; Ngondi 2005). In a randomized controlled trial, 150 mg of a proprietary extract from Irvingia gabonensis, taken twice daily for 10 weeks, significantly decreased body weight, body fat, and waist circumference in overweight subjects. There were also improvements in several metabolic parameters related to insulin resistance, including increased adiponectin and decreased leptin and CRP (Ngondi 2009).
In another trial, a combination of extracts from irvingia and Cissus quadrangularis, a West African vine, produced significantly larger reductions in body weight and fat, total cholesterol, LDL cholesterol, and fasting blood glucose compared with the Cissus extract alone (Oben, Ngondi, Momo 2008).
Nicotinamide riboside. Nicotinamide adenine dinucleotide (NAD+) is a critical regulator of cellular energy (Kim, Oh 2015). It is also a cofactor for sirtuin proteins, which are involved in many metabolic activities and associated with longevity. Aging is associated with declining activity of SIRT1, the gene that encodes the sirtuin 1 protein, and preclinical studies have shown increasing SIRT1 expression prolongs lifespan (Poulose 2015). Age-related decline of NAD+ levels has been associated with a reduction in SIRT1 activity (Braidy 2011; Gomes 2013). NAD+ metabolism is also implicated in the causation and complications of diabetes (Yoshino 2011; Canto 2015; Imai 2009).
Supplementation with nicotinamide riboside, an NAD+ precursor, boosts cellular NAD+ levels (Bogan 2008; Khan 2014). Animal research has shown nicotinamide riboside can improve insulin sensitivity, augment the benefits of exercise, combat neurodegeneration, and mitigate the negative effects of a high-fat diet (Chi 2013; Canto 2012). In an animal model of type 2 diabetes, nicotinamide riboside supplementation reduced liver inflammation and improved glucose control (Lee, Hong 2015).
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